title: Comparison of the inhibition of Escherichia coli and Lactobacillus casei dihydrofolate reductase by 2,4-diamino-5-(substituted-benzyl)pyrimidines: quantitative structure-activity relationships, X-ray crystallography, and computer graphics in structure-activity analysis.
abstract: The inhibition constants (Kiapp) obtained from the action of 44 2,4-diamino-5-(substituted-benzyl)pyrimidines on dihydrofolate reductase (DHFR) from Escherichia coli and Lactobacillus casei bacteria are used to derive quantitative structure-activity relationships (QSAR). These equations bring out a number of differences in the DHFR which can be understood at the atomic level by studying color stereo computer graphics models constructed from the X-ray coordinates of the enzyme-inhibitor complexes. The combination of QSAR and X-ray crystallography interpreted via high-performance computer graphics offers a new level of sophistication to extend our understanding of enzyme-ligand interactions, which, when the crystallography is known, opens up a more scientific approach to drug development.
mesh_terms: D001665:Binding Sites; D003201:Computers; D004926:Escherichia coli / Q000201:enzymology*; D005493:Folic Acid Antagonists; D007780:Lacticaseibacillus casei / Q000201:enzymology*; D008958:Models, Molecular; D011743:Pyrimidines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D005493:Folic Acid Antagonists; D011743:Pyrimidines